Focal Dermal Hypoplasia

Major Findings

Characteristic ectodermal manifestations include the following (see Figure 1):

Figure 1.

Ectodermal manifestations include yellowish-pink areas representing fat herniation (white arrowheads), patchy aplasia (black arrowheads), hyper-/hypopigmentation following lines of Blaschko (black arrows indicating the border), and hypopigmented areas (more...)

• Congenital patchy skin aplasia (95% of individuals) evidenced by atrophic and hypoplastic areas of skin that often follow the lines of Blaschko and appear as depressed regions of pink or white color, often with a fibrous texture.
  Note: The lines of Blaschko correspond to cell migration pathways evident during embryonic and fetal skin development. Like dermatomes, the lines of Blaschko are linear on the limbs and circumferential on the trunk. Unlike dermatomes, the lines of Blaschko do not correspond to innervation patterns.
• Congenital skin hypo- or hyperpigmentation (90%-100%) often following a Blaschko linear distribution
• Congenital nodular fat herniation (60%-70%), evidenced by soft, yellow-pink nodules on the skin (which represent fat nodules in the dermis) that are typically seen on the trunk and extremities
• Congenital ridged, dysplastic, or hypoplastic nails (80%-90%)
• Telangiectasias (~80%) (may be seen on the face, trunk, and extremities)

Characteristic limb malformations [Smith & Hunt 2016] include the following (see Figure 2 and Figure 3):

Figure 2.

Hands showing syndactyly (black arrow) and split-hand malformation (black arrowhead) with only four digits (oligodactyly) on the left hand. The appearance of the left hand has been somewhat modified by partial surgical repair.

Figure 3.

Highly variable limb malformations Feet showing syndactyly (black arrow), split-hand malformation or ectrodactyly (black arrowhead), oligodactyly (3, 6, 7, 8, 10, 11, 12), and distal transverse limb defect (13)

• Syndactyly (70%-90% of individuals) joining or webbing of ≥2 fingers or toes, occurring variably on one or more extremities
• Ectrodactyly (75%), a split hand/foot malformation that may occur on one or more extremities
• Oligodactyly (20%-40%) – <5 digits on a hand or foot, which may be seen in one or both hands or feet. Central digits are more frequently involved.
• Transverse limb defect (15%) – congenital absence of the hand, wrist, forearm, or elbow with no distal remaining portions, including acheiria or hemimelia
• Long bone reduction defect (50%-80%) – hypoplasia or shortening of the long bones in one or more extremities

Minor Findings

Additional common features not included in the diagnostic criteria but supportive of the diagnosis include the following.

Ectodermal manifestations [Bree et al 2016, Wright et al 2016]

• Patchy alopecia of the scalp (80% of individuals) or wiry hair (65%)
• Verrucoid papillomas (65%) of the skin and mucous membranes (including in the mouth, nose, larynx, esophagus, vaginal mucosa, and/or rectal mucosa)
• Dental abnormalities including enamel defects / longitudinal grooving (65%), peg teeth (50%), or hypodontia (80%)
• Photosensitivity (40%)
• Pebbled skin texture (58%)
• Hair shaft abnormalities on scanning electron microscopy (80%-90%)

Ocular manifestations [Gisseman & Herce 2016]

• Iris colobomas (50% of individuals)
• Chorioretinal colobomas (60%)
• Microphthalmia (45%) or anophthalmos (5%-10%)
• Cataracts (10%)
• Nystagmus (30%) or strabismus (20%)

Clinical Findings

Focal dermal hypoplasia can be diagnosed clinically in individuals with three or more characteristic major ectodermal manifestations AND at least one characteristic major limb malformation [Bostwick et al 2016].

Note: (1) Skin manifestations should be congenital in onset to distinguish from a similar skin phenotype seen in Rothmund-Thomson syndrome. (2) Minor findings alone are not sufficient to establish a clinical diagnosis, but when present should increase suspicion for focal dermal hypoplasia.

Molecular Genetic Findings

Identification of a germline heterozygous PORCN pathogenic variant or deletion in a female or somatic mosaic hemizygous PORCN pathogenic variant or deletion in a male (see Table 1) confirms the diagnosis in individuals with characteristic clinical findings and establishes the diagnosis when clinical findings are ambiguous or inconclusive.

Note: Nearly all affected males to date have somatic mosaicism for a hemizygous PORCN pathogenic variant [Grzeschik et al 2007, Wang et al 2007, Lombardi et al 2011]; the one notable exception is two brothers who were hemizygous for an inherited novel PORCN missense variant that was likely a hypomorphic allele [Brady et al 2015].

Tiered molecular testing approaches can include a combination of single-gene testing (sequence analysis and gene-targeted deletion/duplication analysis), chromosomal microarray analysis (CMA), use of a multigene panel, and more comprehensive genomic testing.

First-tier testing. On a blood sample, perform sequence analysis of PORCN. If no pathogenic variant is identified, perform either CMA (if not already performed) to detect large deletions/duplications that include PORCN or gene-targeted deletion/duplication analysis of PORCN if CMA was normal; note, however, that intragenic deletions detected by this method have been reported rarely (see Table 1).

Note: (1) Several females and nearly all males have somatic mosaicism for either a PORCN pathogenic variant or PORCN deletion; therefore, possible mosaicism must be considered when performing sequence analysis (see Second-tier testing). (2) A male with a 47,XXY karyotype and a heterozygous PORCN pathogenic variant on one of the two X chromosomes has been reported [Alkindi et al 2013].

Second-tier testing. If first-tier testing does not detect a PORCN pathogenic variant or deletion, perform sequence analysis and deletion/duplication analysis on saliva or affected tissues (e.g., skin, papillomas, surgical specimens), which increase the sensitivity for detecting somatic mosaicism [Maas et al 2009].

Testing to consider. If first-tier and second-tier testing do not detect a PORCN pathogenic variant or deletion, the following may also be considered:

• A multigene panel that includes PORCN and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Affected Females

Ectodermal manifestations. The most characteristic features of focal dermal hypoplasia are the skin manifestations (Figure 1). The cutaneous findings typically follow the lines of Blaschko and include patchy areas of skin aplasia/hypoplasia, skin hypo- and/or hyper-pigmentation, and nodular fat herniation. The lines of Blaschko represent cell migration pathways that are linear on the limbs and circumferential on the trunk. The lines are classically described as V-shaped overlying the upper spine, S-shaped on the abdomen, and an inverted-U shape from the breast area to the upper arms. These findings are typically evident at birth, but the distribution and severity may change over time. Unilateral involvement has also been reported [Tenkir & Teshome 2010, Maalouf et al 2012, Asano et al 2013].

Other integumentary system abnormalities include wiry hair, sparse hair, patchy alopecia of the scalp, and abnormal nails. The nails can be absent (anonychia), small (micronychia), hypoplastic, or dysplastic, often with longitudinal ridging, splitting, or V-nicking [Bree et al 2016].

Papillomatosis. Papillomas and telangectasias are typically not present at birth but develop with age.

• Verrucoid papillomas are found in the oral mucosa of the mouth, nose, pharynx, larynx, trachea, and esophagus. Large papillomas of the larynx can obstruct breathing during anesthesia or can cause obstructive sleep apnea. Papillomas in the esophagus or larynx can also cause or contribute to severe GERD.
• The vaginal or rectal mucosa are also common sites for papillomas, where they can be confused with genital warts.

Dental abnormalities and eye findings, both of which result from abnormalities in ectodermal appendage development, are described separately below.

Limb and skeletal manifestations. Most individuals with focal dermal hypoplasia have limb malformations noted at birth, including syndactyly, oligodactyly, and split-hand/foot malformation or ectrodactyly (Figure 2 and Figure 3) [Gorlin et al 1963, Goltz et al 1970]. These malformations, which do not change over time, may impair function.

Additionally, reduction defects of the long bones ranging from leg length discrepancies to transverse defects of the distal radius/ulna or tibia/fibula are commonly seen.

Less common limb malformations that may be present at birth and impair function include camptodactyly (contraction deformities of the digits) and brachydactyly (shortening of the digits).

Costovertebral segmentation abnormalities including fused ribs, bifid ribs, and hemivertebrae and butterfly vertebrae are present at birth but are often not evident on physical examination and may only be seen on x-ray of the chest and/or spine. Although these malformations do not typically cause problems in infancy or early childhood, they may cause scoliosis as the child grows. Kyphosis or kyphoscoliosis is seen in approximately 10% of affected individuals [Smith & Hunt 2016]. More often, these segmentation abnormalities do not cause health issues.

Diastasis pubis, an abnormal separation of the symphysis pubis, may be an incidental finding or may present in adolescence or adulthood with pain. The gap between the pubic bones in the average non-pregnant adult is 4-5 mm. An abnormal gap is considered to be 1 cm or more, sometimes with the two bones being slightly out of alignment. In some individuals with focal dermal hypoplasia, diastasis pubis may cause pain with walking or in the symphysis pubis, legs, groin, and lower abdomen.

Fibrous dysplasia of bone (i.e., replacement of medullary bone with trabeculae of woven bone containing fluid-filled cysts embedded in a fibrous matrix) may affect any bone at any time. On x-ray the bone appears radiolucent, with what is classically described as a "ground-glass" appearance. Fibrous dysplasia may be asymptomatic or become evident when it is the site of a pathologic fracture.

Giant cell-like tumors of long bones, reported on occasion, may develop in childhood, adolescence, or adulthood. They typically become evident when a pathologic bone fracture occurs at the site of the lesion [Selzer et al 1974, Joannides et al 1983, Tanaka et al 1990]. In the small number of reports to date, none of these tumors has been malignant.

Osteopathia striata, a striated appearance of the bones evident on plain x-rays, is common and may be seen in childhood, adolescence, and adulthood. It is currently unclear if individuals with this finding are at increased risk for general osteoporosis. Of note, a spontaneous patella fracture related to osteoporosis in a patient with FDH has been reported [Altschuler et al 2012].

Eye findings. Developmental abnormalities of the eyes are common and are evident at birth. Depending on the severity of the manifestations, vision can range from 20/20 to no light perception. Reported eye abnormalities include anophthalmia/microphthalmia; microcornea; iris, chorioretinal and eyelid colobomas; lacrimal duct abnormalities; and cataracts (cortical and subcapsular) [Gorlin et al 1963, Goltz et al 1970].

Strabismus and/or nystagmus can be observed when visual impairment in infancy is significant.

Craniofacial findings. Facial features are variable and include facial asymmetry, notched alae nasi, pointed chin, and small underfolded pinnae. These facial characteristics are not typically evident at birth but develop with time (Figure 4) [Gorlin et al 1963, Goltz et al 1970].

Figure 4.

Note facial features of pointed chin and small right ear.

Cleft lip and palate can be present and may lead to difficulty with feeding. More severe facial clefting can cause feeding, breathing, and vision problems, as well as significant cosmetic concerns [Ascherman et al 2002].

Oral and dental findings. Oral manifestations are seen in more than half of affected individuals and include both soft tissue and hard tissue abnormalities.

Enamel hypoplasia that predisposes to dental caries is the most common problem. Other findings include: hypodontia, oligodontia, supernumerary teeth, and dental crowding leading to malocclusion of both primary and secondary dentition; vertical grooving of the teeth; microdontia (small teeth); taurodontia (prism-shaped molars); fused teeth; and abnormal root morphology [Balmer et al 2004, Tejani et al 2005, Murakami et al 2011]. Affected individuals may also have problems with the eruption and position of teeth. Natal teeth were described in one affected individual [Dias et al 2010].

Soft tissue abnormalities include generalized gingivitis and intra-oral lipomas and papillomas.

Gastrointestinal and nutrition. Problems include poor weight gain (77% of individuals), short stature (65%), oral motor dysfunction (41%), gastroesophageal reflux (24%), gastroparesis (35%), and constipation (35%) [Motil et al 2016]. Food allergies – primarily to milk, soy, and shellfish – are present in 12% of affected individuals.

Other developmental abnormalities of the digestive system are rare but may have severe consequences; they include abdominal wall defects and diaphragmatic hernia (see Congenital Diaphragmatic Hernia Overview).

Severe gastroesophageal reflux disease (GERD) has been reported in infancy and childhood, leading to feeding difficulties with frequent vomiting and/or discomfort/distress. GERD likely results from esophageal papillomas [Brinson et al 1987].

Renal and urogenital. Genital labial hypoplasia is present in most females [Adeyemi-Fowode et al 2016]. Occasional affected individuals with müllerian anomalies, including bicornuate uterus, have been described [Reddy & Laufer 2009, Lopez-Porras et al 2011].

Renal structural abnormalities are uncommon, but previous case reports include unilateral absent kidney, hypoplastic kidney, fused/horseshoe kidney, or cystic renal dysplasia. If present, these abnormalities may lead to recurrent urinary tract infections and urinary reflux [Suskan et al 1990].

Cognitive and psychological. Development and intellectual ability is normal in most individuals. Intellectual impairment (15%-20% of individuals), behavioral problems (~20%), emotional lability (40%-50%), and withdrawn behavior (65%) have been reported [Deidrick et al 2016]. In those with emotional, behavioral, adaptive, and intellectual impairment, the spectrum of severity varies widely.

Structural brain abnormalities and spina bifida [Goltz et al 1970, Almeida et al 1988] have been reported but are uncommon.

Epilepsy has been reported [Kanemura et al 2011].

Other. Mixed conductive and sensorineural hearing loss has been reported on occasion.

When the first affected female in the family has milder manifestations than affected females in subsequent generations [Wechsler et al 1988, Kilmer et al 1993], it is most likely that she has either mosaicism for the PORCN pathogenic variant or skewing of X-chromosome inactivation. Alternative explanations could be reduced reproductive fitness in severely affected females, such that only mildly affected females reproduce.

Affected Males

Because relatively few affected males have been reported, no comprehensive data for a "typical" male phenotype exist.

Affected males may have any of the features seen in affected females including typical skin findings; sparse, brittle hair; nail dystrophy; microphthalmia; syndactyly; split-hand/foot malformation; costovertebral segmentation abnormalities; osteopathia striata; and diastasis pubis [Wang et al 2007, Bornholdt et al 2009, Maas et al 2009, Lombardi et al 2011, Lasocki et al 2011, Vreeburg et al 2011, Yoshihashi et al 2011].

Affected males have somatic mosaicism for a PORCN pathogenic variant and are generally more mildly affected than females [Grzeschik et al 2007, Wang et al 2007, Lombardi et al 2011]. Of note, fathers with focal dermal hypoplasia are typically more mildly affected than their daughters [Burgdorf et al 1981], a discrepancy attributed to mosaicism in the males.

Severe Presentations

Various phenotypes have been previously described as separate syndromes or potentially allelic conditions, but are now recognized to be within the spectrum of focal dermal hypoplasia.

Angioma serpiginosum was initially hypothesized to be allelic to focal dermal hypoplasia [Blinkenberg et al 2007]. A deletion of PORCN was subsequently reported in one affected individual [Houge et al 2008], but this was later disputed and proposed to be a case of FDH instead of a case of angioma serpiginosum [Happle 2009].

According to Van Allen & Myhre [1991], Van Allen-Myhre syndrome was either a severe form of focal dermal hypoplasia or allelic to focal dermal hypoplasia. This has been confirmed in a report in which an individual with Van Allen-Myhre syndrome [Hancock et al 2002] was found to have a pathogenic variant in PORCN [personal observation; case reported by Wang et al 2007].

FDH with abdominal wall closure defects that are in the spectrum of pentalogy of Cantrell or limb-body wall complex anomaly have been reported [Hancock et al 2002, Maas et al 2009, Scott et al 2009, Smigiel et al 2011]. In some of these affected individuals, PORCN pathogenic variants have been detected [Maas et al 2009, Lombardi et al 2011, Smigiel et al 2011]. Whether pathogenic variants in PORCN can cause isolated forms of these conditions has not been established.

Pathology

Histopathologic and ultrastructural studies of the skin have shown the following:

• A thinned dermis with disordered connective tissue and decreased number of collagen bundles and elastin fibers [Kanitakis et al 2003]
• Rests of mature adipose tissue scattered throughout the reticular and papillary dermis [Howell & Freeman 1989, del Carmen Boente et al 2007]. Whether these represent herniation of fat into a thinned dermis or ectopic aggregation of fat within a dysplastic dermis is unclear [Howell & Freeman 1989].
• Verrucoid papillomas that resemble squamous papillomas with hyperplastic, stratified squamous epithelium overlying a fibrovascular core. Verrucoid papillomas lack the typical morphologic evidence of human papilloma virus infection and stain negative for Epstein-Barr virus RNA [Rosen & Bocklage 2005].
• From biopsies from Blaschkoid streaks, findings of increased papillary dermal blood vessels, decreased thickness of the dermis, and adipocytes high in the dermis strongly point to the diagnosis of focal dermal hypoplasia [Ko et al 2016].